Proarrhythmic effects of DL- and D-sotalol on the "border zone" between normal and ischemic regions of isolated ventricular myocardium and antiarrhythmic effects on reperfusion.
Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 microM) in an in vitro model of "border zone" arrhythmias. Isolated guinea-pig ventricular strips were partly exposed to normoxia ("Normal Zone," NZ) and partly to modified Tyrode's solution ("Ischemic Zone," IZ) for 15 or 30 min ("ischemia"), followed by return to normoxia for 30 min ("reperfusion"). Resting membrane potential, action potential (AP) amplitude, and maximal upstroke velocity of AP were not significantly modified. DL- And D-sotalol, 5 and 10 microM, lengthened AP duration 90% (APD90) in NZ (p < 0.05), whereas these drugs were unable to prevent ischemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to control random variability of analyzed covariates, DL- and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (chi2 = 24.79; p = 0.0367): 83 (5 microM D- and DL-sotalol), 86, and 62% (10 microM D- and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 microM DL-sotalol prevented the occurrence of spontaneous arrhythmias (chi2 = 46.74; p = 0.0001) similar to what seen with the beta-blocking agent propranolol (10 microM). These data, providing evidence for proarrhythmic effects of DL- and D-sotalol on border-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study results.
Picard
S
S
Anesthésiologie Expérimentale et Physiologie Cellulaire, UFR de Médecine, Caen University, France.
Rouet
R
R
Monti
F
F
Puddu
P E
PE
Ducouret
P
P
Flais
F
F
Libersa
C
C
Gérard
J L
JL
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D015999:Multivariate Analysis; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D013015:Sotalol